Substituted alkyl uracils and thereof

ABSTRACT

The invention relates to novel compounds of formula (I), to a method for the production thereof, and to their use as medicament active ingredients for the prophylaxis and/or treatment of diseases.

The present invention relates to novel chemical compounds, to a processfor their preparation and to their use as medicaments, in particular forthe prophylaxis and/or treatment of ischemia and reperfusion damage.

The elucidation of the molecular mechanism of cell death is the subjectof intense biomedical research efforts. The aim is to find specificallyactive compounds which have modulating action in this process. When theindividual biochemical steps resulting in cell death were examined,attention was drawn to poly(ADP-ribose)-synthetase (PARS), a proteinwhich is expressed strongly in the cell nucleus and which is involved indeoxyribonucleic acid (DNA) damage repair [Szabo and Dawson, Trends inPharmacological Sciences, 19, 287-298 (1998)].

Activation of PARS plays an important role in N-methyl-D-aspartate(NMDA)- and NO-induced neurotoxicity [Zhang et al., Science, 263,687-689 (1994); Wallis et al., NeuroReport, 5, 245-248 (1993)], cerebralischemia [Endres et al., J. Cereb. Blood Flow Metabol., 17, 1143-1151(1997)], traumatic brain injuries [Wallis et al., Brain Res., 710,169-177 (1996)] and ischemia/reperfusion damage to heart and skeletalmuscle [Thiemermann et al., Proc. Nat. Acad. Sci., 94, 679-683 (1997)].In addition, inhibition of PARS appears to have a positive effect on thetherapy of arthritis [Szabo et al., Japanese J. Pharm., 75, Supp. I:102(1997)], diabetes [Shimabukuro et al., J. Clin. Invest., 100, 290-295(1997)] and endotoxic or septic shock [Zingarelli et al., Shock, 5,258-264 (1996)], radiosensitization of hypoxic tumor cells [Weltin etal., Oncol. Res., 6, 399-403 (1994)], chronic colitis [Jijon et al., Am.J. Physiol. Gastrointest. Liver Physiol., 279, G641-51 (2000)], suddendeafness [Tabuchi et al., Ann. Otol. Rhinol. Laryngol., 110(2), 118-21(2001)], inflammatory pulmonary disorders, such as, for example, asthmaand chronic bronchitis [Cuzzocrea et al., Eur. J. Pharm., 342, 67-76(1998)] and cancer.

PARS, an enzyme which constructs polymeric ADP-ribose units fromnicotinamide adenosine dinucleotide (NAD⁺) as substrate, is activatedwhen the DNA is damaged by single- or double-strand breaks. Thepolymeric ADP-ribose units formed are attached both to PARS itself andto other proteins, for example histones, topoisomerases and polymerases.

Increased activation of PARS results in a massive NAD⁺ consumption. Thestrong decrease of the NAD⁺ concentration and the resulting impedimentof ATP synthesis (decrease of the ATP concentration) causesdeterioration of the energetic state of the cell, which may lead topremature cell death (necrosis).

In the heart, reperfusion of ischemic myocardium results in thegeneration of radicals, neutrophil infiltration, destruction of themyocardial tissue structure, contraction dysfunctions and necrosis. TheH₂O₂ generated during the reperfusion phase reacts rapidly with NO,forming peroxynitrite. NO, peroxynitrite and H₂O₂ cause DNA strandbreaks, thus resulting in overstimulation of PARS.

A further important point in the case of reperfusion damage is theaccumulation of neutrophils in the reperfused myocardium. Activation ofPARS increases the infiltration of neutrophils by stimulating theexpression of P-selectin and ICAM-1.

Healthy PARS knock-out mice capable of reproduction are substantiallyprotected against reperfusion damage. Infiltration of neutrophils isreduced by 50% and the structure of the myocardial tissue remains intactduring the reperfusion phase.

In cases of ischemia and reperfusion damage to the heart and brain,low-molecular-weight PARS inhibitors, such as, for example,3-aminobenzamide and 1,5-dihydroxyisoquinoline, protect the tissueagainst necrotic cell death (reduction of the infarct size by 30 to 48%)and delay myocardial and neuronal dysfunction.

However, the PARS inhibitors hitherto tested in animal experiments havevarious disadvantages. Thus, for example, 3-aminobenzamide is anunspecific PARS inhibitor which also inhibits cytochrome P₄₅₀ (Erikssonet al., Toxicology and applied Pharmacology, 136, 324-331 (1996)); incontrast, 5-iodo-6-amino-1,2-benzopyrone has serious side-effects (Szaboand Dawson, Trends in Pharmacol. Sciences, 19, 287-298 (1998)).Moreover, most inhibitors are not very potent and are therefore onlyefficacious in animals at a relatively high dosage (Thiemermann et al.,Proc. Natl. Acad. Sci., 94, 679-683.(1997)).

JP-A-032645679 and Chem. Pharm. Bull. 38 (10), 2726-2732 (1990) disclosebicyclic 2,4-(1H,3H)-pyrimidinediones as 5-HT₂ antagonists for thetreatment of cardiovascular diseases, depression and other mentaldisorders. U.S. Pat. No. 5,859,014 discloses tetrahydroquinazolinedionederivatives as α₁ adrenergic receptor antagonists for the treatment ofprostate hypertrophy. WO-A-00/42025 describes dihydropyrimidinones asPARS inhibitors. DE-A-1959705 and DE-A-2126148 list uracil derivativesfor preparing crop protection agents. DE-A-2142317 mentions uracilderivatives having hypnotic properties. Furthermore, various bridgeduracils are described in the literature as nucleoside analogues withpotential antiviral action (for example Nucleosides Nucleotides 13(1-3), 177-196; 13 (4), 891-902 (1994) and J. Med. Chem. 39 (3), 789-795(1996)).

Accordingly, it is an object of the present invention to provide novelsubstances for the prophylaxis and/or treatment of disorders, inparticular of ischemia and reperfusion damage.

Here, the compounds according to the invention act as inhibitors ofpoly(ADP-ribose)-synthetase (PARS).

The present invention relates to compounds of formula (I)

in which

-   -   A represents —CH₂—, —O— or —S—,    -   R¹ represents hydrogen or alkoxycarbonyl,    -   R² represents aryl or heteroaryl which for their part may be        substituted up to three times, independently of one another, by        substituents selected from the group consisting of nitro,        halogen, cyano, aryl, hetaryl, benzyl, alkyl, cycloalkyl,        alkoxy, formyl, alkoxycarbonyl, trifluoromethyl, di- and        trifluoromethoxy, hydroxyl, amino, alkylamino, aminosulfonyl,        alkylsulfonylamino, arylsulfonylamino, hetarylsulfonylamino,        —Y—OR³ and —Y—NR³R⁴,        -   in which        -   Y represents CH₂, C(═O) or —NH—C(═O)—CHR⁵—,            -   in which * represents the point of attachment to the                aromatic or heteroaromatic radical,        -   R³ and R⁴ independently of one another represent hydrogen,            optionally hydroxyl- or amino-substituted alkyl, alkenyl or            alkoxycarbonyl or        -   R³ and R⁴ together with the nitrogen atom to which they are            attached form a 5- to 7-membered heterocycle which may            contain a further heteroatom N, O or S in the ring and which            is optionally substituted by amino, hydroxyl, alkoxycarbonyl            or alkyl which for its part may be substituted by hydroxyl            or amino,        -   R⁵ represents hydrogen or alkyl which for its part may be            substituted by phenyl, 4-hydroxyphenyl, amino, hydroxyl,            carboxyl, guanidino, imidazolyl, indolyl, mercapto or            methylthio, or        -   R³ and R⁵ together represent propane-1,3-diyl or            butane-1,4-diyl, and    -   X represents alkanediyl in which one methylene group may be        replaced by an oxygen atom.

The compounds according to the invention can also be present in the formof their salts, solvates or solvates of the salts.

Depending on their structure, the compounds according to the inventioncan exist in stereoisomeric forms (enantiomers, diastereomers).Accordingly, the invention also relates to the enantiomers ordiastereomers and to their respective mixtures. From such mixtures ofenantiomers and/or diastereomers, the stereoisomerically uniformcomponents can be isolated in the known manner.

Depending on the structure of the compounds, the invention also relatesto tautomers of the compounds.

Preferred salts in the context of the invention are physiologicallyacceptable salts of the compounds according to the invention.

Physiologically acceptable salts of the compounds (I) include acidaddition salts of mineral acids, carboxylic acids and sulfonic acids,for example salts of hydrochloric acid, hydrobromic acid, sulfuric acid,phosphoric acid, methanesulfonic acid, ethanesulfonic acid,toluenesulfonic acid, benzenesulfonic acid, naphthalene-disulfonic acid,acetic acid, propionic acid, lactic acid, tartaric acid, malic acid,citric acid, fumaric acid, maleic acid and benzoic acid.

Physiologically acceptable salts of the compounds (I) also include saltsof customary bases, such as, by way of example and by way of preference,alkali metal salts (for example sodium and potassium salts), alkalineearth metal salts (for example calcium and magnesium salts) and ammoniumsalts, derived, from ammonia or organic amines having 1 to 16 carbonatoms, such as, by way of example and by way of preference, ethylamine,diethyl amine, triethylamine, ethyldiisopropylamine, monoethanolamine,diethanolamine, triethanolamine, dicyclohexylamine,dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine,dihydroabiethylamine, arginine, lysine, ethylenediamine andmethylpiperidine.

Solvates in the context of the invention are those forms of thecompounds which, in the solid or liquid state, form a complex bycoordination with solvent molecules. Hydrates are a specific form of thesolvate where the coordination is with water.

In, the context of the present invention, the substituents are, unlessspecified otherwise, as defined below:

Alkyl per se and “alk” and “alkyl” in alkoxy, alkylaminoalkylsulfonylamino and alkoxycarbonyl denote a linear or branched alkylradical having generally 1 to 6, preferably 1 to 4, particularlypreferably 1 to 3, carbon atoms, by way of example and by way ofpreference methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-pentyl andn-hexyl.

Alkoxy denotes, by way of example and by way of preference, methoxy,ethoxy, n-propoxy, isopropoxy, tert-butoxy, n-pentoxy and n-hexoxy.

Alkylamino denotes an amino radical having one or two alkyl substituentschosen independently of one another, by way of example and by way ofpreference methylamino, ethylamino, n-propylamino, isopropylamino,tert-butylamino, n-pentylamino, n-hexylamino, N,N-dimethylamino,N,N-diethylamino, N-ethyl-N-methylamino, N-methyl-N-n-propylamino,N-isopropyl-N-n-propylamino, N-t-butyl-N-methylamino,N-ethyl-N-n-pentylamino and N-n-hexyl-N-methylamino.

Alkylsulfonylamino denotes, by way of example and by way of preference,methylsulfonylamino, ethylsulfonylamino, n-propylsulfonylamino,isopropyl-sulfonylamino, tert-butylsulfonylamino, n-pentylsulfonylaminoand n-hexyl-sulfonylamino.

Alkoxycarbonyl denotes, by way of example and by way of preference,methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl,tert-butoxycarbonyl, n-pentoxycarbonyl and n-hexoxycarbonyl.

Alkanediyl denotes a straight-chain or branched alkanediyl radicalhaving generally 1 to 6, preferably 1 to 4, carbon atoms, by way ofexample and by way of preference. methylene, ethane-1,2-diyl,propane-1,2-diyl, propane-1,3-diyl, propane-2,2-diyl, butane-1,3-diyl,butane-1,4-diyl, butane-2,4-diyl, pentane-2,4-diyl,2-methylpentane-2,4-diyl.

If a methylene group of the alkanediyl radical is substituted by anoxygen atom, the following radicals may be mentioned by way of exampleand by way of preference: 3-oxabutane-1,4-diyl, 4-oxabutane-1,4-diyl,3-oxapentane-1,5-diyl, 4-oxapentane-1,5-diyl, 4-oxahexane-1,6-diyl.

Alkenyl denotes a straight-chain or branched alkenyl radical havinggenerally 2 to 6, preferably 2 to 4, particularly preferably 2 or 3,carbon atoms, by way of example and by way of preference vinyl, allyl,n-prop-1-en-1-yl, n-but-2-en-1-yl.

Cycloalkyl denotes a cycloalkyl group having generally 3 to 8,preferably 5 to 7, carbon atoms, by way of example and by way ofpreference cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl andcycloheptyl.

Aryl per se and “aryl” in arylsulfonylamino denotes a mono-, bi- ortricyclic aromatic carbocyclic radical having generally 6 to 14 carbonatoms; by way of example and by way of preference phenyl, naphthyl andphenanthrenyl.

Arylsulfonylamino denotes, by way of example and by way of preference,phenylsulfonylamino, naphthylsulfonylamino andphenanthrenylsulfonylamino.

Heteroaryl per se and “hetaryl” in hetarylsulfonylamino denotes anaromatic, optionally benzo-fused radical having generally 5 or 6 ringatoms and up to 3 heteroatoms from the group consisting of S, O and N,by way of example and by way of preference thienyl, furyl, pyrrolyl,thiazolyl, oxazolyl, pyrazolyl, imidazolyl, isoxazolyl, isothiazolyl,pyridyl, pyrimidyl pyridazinyl, pyrazinyl, indolyl, indazolyl,benzofuranyl, benzothiophenyl, quinolinyl, isoquinolinyl.

Hetarylsulfonylamino denotes, by way of example and by way ofpreference, pyridylsulfonylamino, thienylsulfonylamino andpyrazolylsulfonylamino.

Halogen denotes fluorine, chlorine, bromine and iodine.

Preference is given to compounds of the formula (I),

-   -   in which    -   A represents —CH₂— or —S—,    -   R¹ represents hydrogen,    -   R² represents phenyl, pyridyl, pyrazolyl or imidazolyl which for        their part may be substituted up to three times, independently        of one another, by substituents selected from the group        consisting of nitro, halogen, phenyl, benzyl, (C₁-C₄)-alkyl,        (C₁-C₄)-alkoxy, formyl, (C₁-C₄)-alkoxycarbonyl, amino, hydroxyl,        aminosulfonyl and —Y—NR³R⁴,        -   in which        -   Y represents CH₂, *—NH—C(═O)—CH₂— or *—NH—C(═O)—CH(CH₃)—,            -   in which * represents the point of attachment to the                aromatic or heteroaromatic radical,        -   R³ and R⁴ independently of one another represent hydrogen,            optionally hydroxyl- or amino-substituted (C₁-C₄)-alkyl,            (C₂-C₄)-alkenyl or (C₁-C₄)-alkoxycarbonyl or        -   R³ and R⁴ together with the nitrogen atom to which they are            attached form a 5- to 7-membered heterocycle which may            contain a further heteroatom N or O in the ring and which is            optionally substituted by amino, hydroxyl,            (C₁-C₄)-alkoxycarbonyl or (C₁-C₄)-alkyl which for its part            may be substituted by hydroxyl or amino, and    -   X represents (C₁-C₄)-alkanediyl.

Particular preference is given to compounds of the formula (I),

-   -   in which    -   A represents —S—,    -   R¹ represents hydrogen,    -   R² represents phenyl or imidazolyl which for their part may be        substituted up to three times, independently of one another, by        substituents selected from the group consisting of nitro,        fluorine, chlorine, bromine, methyl, ethyl, isopropyl,        methoxycarbonyl and —Y—NR³R⁴,        -   in which        -   Y represents CH₂ or *—NH—C(═O)—CH₂—,            -   in which * represents the point of attachment to phenyl                or imidazolyl,        -   R³ and R⁴ independently of one another represent hydrogen,            methyl, ethyl, isopropyl which are optionally substituted by            hydroxyl or amino, or represent allyl or methoxycarbonyl,        -   or        -   R³ and R⁴ together with the nitrogen atom to which they are            attached represent pyrrolidin-1-yl, piperidin-1-yl,            piperazin-1-yl, 4-methyl-piperazin-1-yl,            4-(2-hydroxyethyl)piperazin-1-yl or morpholin-4-yl and    -   X represents ethane-1,2-diyl; propane1,3-diyl or        butane-1,4-diyl.

The present invention also provides a process for preparing thecompounds of the formula (I) where

-   -   compounds of the formula (II)        in which    -   A is as defined above,    -   are reacted with compounds of the formula (III)        H₂N—X—R²   (III),        in which    -   X and R² are as defined above,    -   to give compounds of the formula (IV)        in which    -   A, X and R² are as defined above,    -   then reacted with chlorocarbonyl isocyanate to give compounds of        the formula (Ia)        in which    -   A, X and R² are as defined above and R¹ represents hydrogen,    -   and compounds of the formula (Ia) are, if appropriate, reacted        with compounds of the formula (V)        R¹-Z   (V),        in which    -   R¹ is as defined above, but is not hydrogen, and Z represents a        leaving group,    -   to give compounds of the formula (I) in which R¹ is not        hydrogen.

The resulting compounds of the formula (I) can then be subjected tofurther derivatizations carried out by customary methods.

The compounds of the formula (I) obtained in this manner can then, ifappropriate, be converted into the corresponding salts, for example byreaction with an acid.

The process according to the invention for preparing compounds of theformula (I) can be illustrated in an exemplary manner by the formulascheme below:

The compounds of the formula (III) are commercially available, knownfrom the literature or can be prepared by customary methods oranalogously to the reaction steps described in the examples. If R² isheteroaryl which is attached via a nitrogen atom, compounds of theformula (III) can be prepared, for example,

-   -   by reacting compounds of the formula (VI)        R²—H   (VI),        in which    -   R² represents heteroaryl which is attached via a nitrogen atom        to the hydrogen atom,    -   with compounds of the formula (VII)        in which    -   X is as defined above and Z¹ represents a leaving group,    -   to give compounds of the formula (VIII)        followed by removal of the phthalimide group.

The reaction sequence is illustrated by the reaction scheme below:

Suitable solvents for the processes described above are organic solventswhich are inert under the reaction conditions, or water. These includehalogenated hydrocarbons, such as dichloromethane, trichloromethane,carbon tetrachloride, 1,2-dichloroethane, trichloroethane,tetrachloroethane, 1,2-dichloroethylene or trichloroethylene, ethers,such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl etheror diethylene glycol dimethyl ether, hydrocarbons, such as benzene,xylene, toluene, hexane or cyclohexane, or other solvents, such asdimethyl-formamide, dimethyl sulfoxide, N-methylpyrrolidone,acetonitrile or pyridine, or mixtures thereof.

The reactions are generally carried out in a temperature range of from−78° C. to 150° C.

The reactions can be carried out under atmospheric pressure, elevatedpressure or reduced pressure (for example in the range from 0.5 to 5bar). In general, the reactions are carried out under atmosphericpressure.

Suitable bases are the customary inorganic or organic bases. Thesepreferably include alkali metal and alkaline earth metal hydroxides,such as, for example, lithium, sodium hydroxide or potassium hydroxide,or alkali metal and alkaline earth metal carbonates, such as sodiumcarbonate or potassium carbonate, or sodium methoxide or potassiummethoxide or sodium ethoxide or potassium methoxide or potassiumtert-butoxide, or amides, such as sodium amide, lithiumbis(trimethylsilyl)amide or lithium diisopropylamide, or amines, such astriethylamine, diisopropylethylamine, diisopropylamine,N-methylmorpholine, 4-dimethylaminopyridine or pyridine.

The reaction step (II)+(III)→(IV) is preferably carried out in thesolvent toluene. For this reaction, the temperature range is inparticular between 80° C. and 120° C. Moreover, the reaction can, ifrequired, be accelerated by addition of catalytic amounts of acid,preferably an organic sulfonic acid, in particular camphorsulfonic acid.

The reaction of compounds (IV) with chlorocarbonyl isocyanate to givecompounds (Ia) is preferably carried out in the solvent toluene. Here,the addition of chlorocarbonyl isocyanate is preferably carried out atroom temperature, further reaction is then carried out in particular ina temperature range between 80° C. and 120° C.

In the reaction (Ia)+(V)→(I), a suitable leaving group Z for compoundsof the formula (V) is, for example: halogen or 1-imidazolyl. Preferenceis given to chlorine.

The reaction (VI)+(VII)→(VIII) is preferably carried out in the solventdimethyl-formamide using the base potassium carbonate. The preferredtemperature range for this reaction is between 20° C. and 130° C.Suitable leaving groups Z′ in compounds of the formula (VII) are, forexample, halogen, mesylate, tosylate or triflate; preference is given tobromine.

The compounds of the formula (VIII) obtained in the reaction above are,preferably in the solvent ethanol and using aqueous hydrazine hydratesolution in a temperature range of from 50° C. to 80° C., reactedfurther, with removal of the phthalimide group. By adding an acid,preferably a hydrochloric acid, the amines of the formula (III) can beobtained in the form of their salts.

The compounds of the formulae (II), (V), (VI) and (VII) are commerciallyavailable, known from the literature or can be prepared by customarymethods or analogously to the reaction steps described in the examples.

Surprisingly, the compounds of the formula (I) have an unforeseeableuseful spectrum of pharmacological and pharmacokinetic activity, andthey are therefore particularly suitable for the prophylaxis and/ortreatment of disorders in humans and animals.

Owing to their pharmacological properties, the compounds according tothe invention can be used on their own or in combination with otheractive compounds, preferably for the prophylaxis and/or treatment ofischemic and reperfusion damage in the heart (after an acuteinfarction), in the brain (after a stroke) or in skeletal muscle, forcardiovascular disorders, such as, for example, unstable angina pectorisand arteriosclerosis, neuronal and neurodegenerative disorders, such as,for example, epilepsy, chronic pain, Alzheimer's disease and Parkinson'sdisease, traumatic brain injuries, septic shock, and also arthritis,diabetes, chronic colitis, sudden deafness, inflammatory pulmonarydisorders, such as, for example, asthma and chronic bronchitis, andcancer.

The present invention also relates to medicaments comprising at leastone compound according to the invention, preferably together with one ormore pharmaceutically acceptable auxiliaries, and to their use for thepurposes mentioned above.

The present invention furthermore relates to a method for theprophylaxis and/or treatment of the clinical pictures mentioned aboveusing the substances of the formula (I).

In addition, the compounds according to the invention can be used forthe treatment of acute myocardial infarction, including in combinationwith one or more of the following medicaments which are used for thestandard therapy of acute myocardial infarction: calcium canal blockers(such as, for example, nifedipine, diltiazem, verapamil),nitrovasodilators (such as, for example, isosorbide dinitrate, glyceroltrinitrate, isosorbide 5-mononitrate, molsidomine), beta blockers (suchas, for example, metoprolol, atenolol, propranolol, solatol), plateletaggregation inhibitors (such as, for example, acetylsalicylic acid,triclopidine, clopidrogrel), thrombolytics (fibrinolytics) (such as, forexample, streptokinase, alteplase, reteplase, urokinase, anistreplase),anticoagulants (such as, for example, heparin, warfarin,phenprocoumarin, low-molecular-weight heparins), ACE inhibitors (suchas, for example, enalapril), glycoprotein IIb/IIIa receptor antagonists(such as, for example, tirofiban, eptifibatid), antiarrhythmics (suchas, for example, lidocaine, amiodarone) and beta-adrenergic agonists(such as, for example, dopamine, dobutamine).

The active compound can act systemically and/or locally. To this end, itcan be administered in a suitable manner, such as, for example, orally,parenterally, pulmonarily, nasally, sublingually, lingually, buccally,rectally, transdermally, conjunctivally, otically or as an implant, forexample in the form of an active compound-containing stent.

For these administration routes, the active compound can be administeredin suitable administration forms.

Administration forms suitable for oral administration are knownadministration forms which release the active compound rapidly and/or inmodified form, such as, for example, tablets (uncoated and also coatedtablets, for example enterically coated tablets or film-coated tablets),capsules, sugar-coated tablets, granules, pellets, powders, emulsions,suspensions, solutions and aerosols.

Parenteral administration can be effected by circumventing abioabsorption step (in an intravenous, intraarterial, intracardial,intraspinal or intralumbal manner), or via bioabsorption(intramuscularly, subcutaneously, intracutaneously, percutaneously orintraperitoneally). Administration forms suitable for parenteraladministration are, inter alia, preparations for injection and infusionin the form of solutions, suspensions, emulsions, lyophilizates andsterile powders.

Medicinal forms suitable for the other administration routes are, forexample, medicinal forms for inhalation (inter alia powder inhalators,nebulizers), nasal drops/solutions, sprays; capsules or tablets to beadministered lingually, sublingually or buccally, suppositories,preparations for ears or eyes, vaginal capsules, aqueous suspensions(lotions, agitated mixtures), lipophilic suspensions, ointments, creams,milk, pastes, powder for spreading or implants.

The active compounds can be converted in a manner known per se into theadministration forms listed. This is effected using pharmaceuticallysuitable auxiliaries. These include, inter alia, excipients (for examplemicrocrystalline cellulose), solvents (for example liquid polyethyleneglycols), emulsifiers (for example sodium dodecyl sulfate), dispersants(for example polyvinylpyrrolidone), synthetic and natural biopolymers(for example albumin), stabilizers (for example antioxidants such asascorbic acid), colorants (for example inorganic pigments, such as ironoxides), or flavor- and/or odor-masking substances.

In the pharmaceutical preparations listed above, the therapeuticallyactive compounds should be present in a concentration of from about 0.1to 99.5, preferably from about 0.5 to 95, % by weight of the totalmixture, i.e. the active compound should be present in amountssufficient to achieve the dosage range indicated.

In general, it has been found to be advantageous both in human andveterinary medicine to administer the active compound(s) according tothe invention in total amounts of from about 0.01 to about 100,preferably from 0.05 to 50, mg/kg of body weight per 24 hours, ifappropriate in the form of a plurality of individual doses, to obtainthe desired results. An individual dose preferably comprises the activecompound(s) according to the invention in amounts of from about 0.01 to50, in particular from 0.1 to 10, mg/kg of body weight.

In spite of this, it may be necessary, if appropriate, to depart fromthe amounts mentioned, namely depending on the body weight or theadministration route, on the individual response to the medicament, themanner of its formulation and the time or interval at whichadministration takes place. Thus, in some cases it may be adequate tomanage with less than the abovementioned minimum amount, while in othercases the upper limit mentioned has to be exceeded. If relatively largeamounts are administered, it may be advisable to divide these into anumber of individual administrations over the day.

Unless indicated otherwise, all percentages in the tests and examplesbelow are based on weight; parts are parts by weight. Solvent ratios,dilution ratios and stated concentrations of liquid/liquid solutions arein each case based on volume.

A Evaluation of the Physiological Activity

1) Test Description PARS Inhibition Test (In Vitro)

The activity of substances as PARS inhibitors is tested in accordancewith the method of Ushiro [Ushiro et al., J. Biol. Chem., 262, 2352-2357(1987)]. To this end, recombinantly expressed (Bac-To-Bac, Baculo virusexpression system; Instruction Manual; Life Technologies) human PARSenzyme is activated in a buffer which contains radioactively labeled[¹⁴C]-NAD⁺. The poly(ADP-ribose) units that are synthesized areprecipitated using trichloroacetic acid, and the proportion of labeledprotein is determined by scintillation measurements. Incubation of PARSwith inhibitors leads to a decrease in the proportion of labeled proteinand thus to a reduced radioactivity.

Inhibition of the PARS activity can be represented as a percentage ofPARS inhibition in incubation with different substances or as theconcentration at which 50% of the enzyme is inhibited, i.e. as IC₅₀value. Material Buffer: 100 mM 2-amino-2-hydroxymethyl-1,3-propanediol(tris)-HCl, pH 7.4  10 mM MgCl₂  1 mM dithiothreitol (DTT) Tris-HCl andMgCl₂ are dissolved in water, DTT is added from an aqueous 100 mM stocksolution (stored at −20° C.) and the pH is adjusted with concentratedHCl to 7.4. DNA: 1 mg/ml of calf thymus DNA 1 mg/ml of calf thymus DNA(from Sigma) is dissolved in water and sonicated to induce strandbreaks. 500 μl aliquots were stored at −20° C. Histones: 10 mg/ml oftype IIA histones, calf thymus 10 mg/ml of lyophilized histones (fromSigma) are dissolved in water. 500 μl aliquots are stored at −20° C.NAD⁺ Mix: 2 mM NAD⁺ in buffer, NAD⁺ (from Sigma) solutions are preparedfreshly before each test. In each case 3 μl of labeled [¹⁴C]-NAD⁺ (2.8kBq, from Amersham) are added to 7 μl of cold NAD⁺ solution.Trichloroacetic acid (TCA): TCA is stored at 4° C. as a 10% strength byweight solution. PARS: Human PARS protein is expressed recombinantly inthe baculovirus system (Bac-To-Bac, Baculo virus expression system;Instruction Manual; Life Technologies) and purified. 500 μl aliquots arestored at −80° C.Methods

The compounds to be tested are dissolved in DMSO (dimethyl sulfoxide) ata concentration of 10 mM. The assay is carried out in deep 96-wellplates. Per well, 70 μl of buffer, 10 μl of DNA, 10 μl of histones, 10μl of NAD⁺/[¹⁴C]-NAD⁺ mix and 0.5-5 μl of PARS (about 10,000 cpm/test)are combined with 1 μl of the compounds (final concentration 0.001-10μM), to give a total volume of about 110 μl. The mixture is incubated atroom temperature for 10 min, and 1 ml of ice-cold TCA solution is thenadded, and the precipitated labeled proteins are sucked onto a filterpaper (printed filter mat A; from Wallac) using a harvester (fromScatron). The filter is dried, sealed together with a scintillationsheet (Multilex A; from Wallac) and measured in a p counter for 1 minper well.

Results of the PARS Inhibition Test

In addition to the substances described in this application, the knownPARS inhibitor 1,5-dihydroxyisoquinoline (DHCH) is tested as referencesubstance. The results of the test are stated as IC₅₀ values for theinhibition of PARS.

The results are shown in Table 1: TABLE 1 PARS inhibition (in vitro)Example IC₅₀ [nM] DHCH 300  1 60  6 50  8 85 40 20 53 80 56 75 62 8002) Test Description Cell Protection Assay (In Vitro)

In accordance with a method described by Bowes [Bowes et al., Br. J.Pharmacol., 124, 1760-1766 (1998)], the ability of PARS inhibitors toprotect cells against cell death induced by incubation with H₂O₂ isexamined in a cell protection assay. Incubation of endothelial cellswith H₂O₂ results in the generation of DNA strand breaks which in turnactivate PARS, resulting in a drastic energy decrease in the cells andin cell death. Living cells are quantified by a fluorimetric redoxindicator (Alamar blue), which is converted in the electron transportsystem of the mitochondria.

Specifically, 7500 MHEC5-T cells/well (DSM ACC 336; German collection ofmicroorganisms and cell cultures) are sown in 4 replications on a96-well plate. After 24 hours, the cells are incubated with 3 mM aqueousH₂O₂ solution and differing concentrations of the substances in thepresence of 6% by volume of Alamar blue solution in the medium at 37° C.for 5 hours. The reference substance used is 10 μM1,5-dihydroxyisoquinoline (DHCH) solution. After the incubation, thefluorescence is measured at an excitation wavelength of 530-560 nm andan emission wavelength of 590 nm. The percentage for the cell protectionis calculated as the difference between the living cells treated onlywith H₂O₂ and the cells treated with H₂O₂ and PARS inhibitors. Theinternal standard used is 10 μM DHCH, which is defined as 100%protection. The results obtained for the other substances are comparedto this value.

Results of the Cell Protection Assays:

Examples of the protection of endothelial cells by PARS inhibitors arelisted in Table 2 below. The EC₅₀ values indicate the concentration atwhich 50% of maximum cell protection is reached, maximum protection by10 μM DHCH being defined as 100%. DHCH has an EC₅₀ value of 2 μM. TABLE2 Cell protection (in vitro) Example EC₅₀ [nM] 5 150 61 100 65 90 66 65076 5003) Test Description “Working Heart” Model (In Vivo)

For tests on isolated hearts in the “working heart” mode [Bardenheuerand Schrader, Circulation Res., 51, 263 (1983)], isolated hearts of ratsare subjected to a 60-minute “low-flow” phase to generate globalischemia, and the action of the substances with respect to thereestablishment of the pressure in the left ventricle (LVPmax) and thecontractile force (dP/dt) during the reperfusion phase is examined. Thecontrol substance used is 1,5-dihydroxyisoquinoline.

B. Working Examples:

In the description of the examples, the following abbreviations areused:

-   -   DMF=N,N-Dimethylformamide    -   DMAP=4-Dimethylaminopyridine    -   EDC=N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride    -   HOBt=1-Hydroxy-1H-benzotriazole

EXAMPLE 11-[2-(4-Bromophenyl)ethyl]-1,5,7,8-tetrahydro-2H-thiopyrano[4,3-d]pyrimidine-2,4(3H)-dione

10 g (50.0 mmol) of 4-(bromophenyl)ethylamine and 6.39 g (55.0 mmol) oftetrahydrothiopyran-4-one are initially charged in 250 ml of toluene, aspatula tip of camphor sulfonic acid is added and the mixture is heatedunder reflux on a water separator for 1.5 hours. The reaction solutionis then allowed to cool under argon, and 4.0 ml (50.0 mmol) ofchlorocarbonyl isocyanate are added at room temperature. The reactionmixture is heated at 100° C. for one hour and cooled, and the solvent isthen removed under reduced pressure. A sodium bicarbonate solution isadded to the resulting residue and the mixture is extracted three timeswith dichloromethane. The organic phase is washed with saturated sodiumchloride solution and dried over sodium sulfate. The solvent is thenremoved under reduced pressure and the resulting residue is crystallizedfrom ethyl acetate. The product is filtered off and washed with diethylether. This gives 13.9 g (37.8 mmol, yield: 74% of theory) of a solid.

¹H NMR (300 MHz, DMSO-d₆): δ=2.44-2.55 (m, 2H), 2.73-2.92 (m, 6H),3.34-3.43 (m, 2H), 3.92 (t, 2H), 7.21 (d, 2H), 7.50 (d, 2H), 11.46 (s,1H)

MS (ESIpos): m/z=366.7 (M+H)⁺

EXAMPLE 2 Methyl4-[2-(2,4-dioxo-3,4,7,8-tetrahydro-2H-thiopyrano[4,3-d]pyrimidin-1(5H)-ylethyl]benzoate

62 mg (0.15 mmol) of 1,3-bis(diphenylphosphino)propane and 31 mg (0.14mmol) of palladium(II) acetate are initially charged in a flask whichhad been dried by heating. The flask is flushed with carbon monoxidegas, and a solution of 500 mg (1.36 mmol) of the compound from example 1in DMF (15 ml) is then transferred into the prepared flask. 1.90 ml(13.6 mmol) of triethylamine and 10 ml (246.8 mmol) of methanol areadded, and the reaction mixture is heated at 120° C. After a reactiontime of five hours, the solution is allowed to cool and a little wateris added. The solution is then extracted three times with ethyl acetate,and the organic phase is washed with water and saturated sodium chloridesolution and dried over sodium sulfate. Following filtration and removalof the solvent under reduced pressure, the resulting residue iscrystallized from diethyl ether/ethyl acetate. This gives 366 mg (1.1mmol, yield: 78% of theory) of the title compound.

¹H NMR (300 MHz, DMSO-d₆): δ=2.70-2.90 (m, 4H), 2.95 (t, 2H), 3.35 (s,2H), 3.83 (s, 3H), 3.97 (t, 2H), 7.40 (d, 2H), 7.91 (d, 2H), 11.43 (s,1H)

MS (ESIpos): m/z=346.8 (M+H)⁺

EXAMPLE 34-[2-(2,4-Dioxo-3,4,7,8-tetrahydro-2H-thiopyrano[4,3-d]pyrimidin-1(5H)-yl)-ethyl]benoicacid

200mg (8.4 mmol) of lithium hydroxide are added to a solution of 580 mg(1.67 mmol) of the compound from example 2 in methanol (27 ml) and water(9 ml), and the reaction mixture is then heated at 50° C. After areaction time of four hours, the methanol is removed under reducedpressure. The pH of the aqueous phase that remains is adjusted to pH 1using aqueous hydrochloric acid (6 N) (ice bath cooling). The mixture isthen extracted three times with dichloromethane and the organic phase iswashed with saturated sodium chloride solution and dried over sodiumsulfate. After filtration and removal of the solvent under reducedpressure, the resulting residue is purified by preparative HPLC (column:Kromasil 100 C 18.5 mm; 250×40 mm; mobile phase: acetonitrile/water;flow rate: 50 ml/min; UV detection at 254 nm). This gives 210 mg (0.63mmol, yield: 38% of theory) of the title compound as a colorless solid.

¹H NMR (300 MHz, DMSO-d₆): δ=2.82 (s, 4H), 2.93 (t, 2H), 3.18 (s, 2H),3.96 (t, 2H), 7.36 (d, 2H), 7.88 (d, 2H), 11.45 (s, 1H), 12.91 (s, 1H)

MS (ESIpos): m/z 332.7 (M+H)⁺

EXAMPLE 41-{2-[4-(1-Piperazinylcarbonyl)phenyl]ethyl}-1,5,7,8-tetrahydro-2H-thiopyrano[4,3-d]pyrimidine-2,4(3H)-dione

A solution of 50 mg (0.15 mmol) of the compound from example 3, 22 mg(0.17 mmol) of HOBt and 33 mg (0.17 mmol) of EDC in DMF (5 ml) isstirred at room temperature for 30 minutes. 26 mg (0.30 mmol) ofpiperazine, 46 mg of 4-methylmorpholine (0.45 mmol) and a spatula tip ofDMAP are added to this solution, and the mixture is stirred at roomtemperature overnight. After filtration, the reaction solution isdirectly separated by preparative HPLC (column: Kromasil 100 C 18.5 mm;250×40 mm; mobile phase: acetonitrile/water; flow rate: 25 ml/min; UVdetection at 254 nm). This gives 11.5 mg (24.4 mmol, yield: 16% oftheory) of the title compound.

¹H NMR (300 MHz, DMSO-d₆): δ=2.65-2.70 (m, 6H), 2.70-2.82 (m, 2H), 2.90(t, 2H), 3.33 (s, 2H), 3.38-3.68 (m, 4H), 3.95 (t, 2H), 7.30 (d, 2H),8.30 (d, 2H)

MS (ESIpos): m/z=401.3 (M+H)⁺

EXAMPLE 54-[2-(2,4-Dioxo-3,4,7,8-tetrahydro-2H-thiopyrano[4,3-d]pyrimidin-1(5H)-ylethyl]benzaldehyde

A solution of 1 g (2.7 mmol) of the compound from example 1 intetrahydrofuran (50 ml) is cooled to −78° C. 3.5 ml (5.58 mmol) of asolution of n-butyllithium (1.6 M) in n-hexane are added dropwise,followed by the addition of 3.1 g (27.2 mmol) of n-formylpiperidine.After the addition, the mixture is warmed to −20° C. and stirred for 18h. The reaction mixture is then warmed to −10° C., and 10 ml of waterare added. The aqueous phase is then extracted three times withdichloromethane and the combined organic phases are washed withsaturated sodium chloride solution and dried over sodium sulfate. Afterremoval of the solvent under reduced pressure, the resulting residue ispurified by preparative HPLC (column: Kromasil 100 C 18.5 mm; 250×40 mm;mobile phase: acetonitrile/water; flow rate: 50 ml/min; UV detection at254 nm). This gives 257 mg (0.81 mmol, yield: 30% of theory) of thetitle compound.

¹H NMR (300 MHz, DMSO-d₆): δ=2.76-2.86 (m, 4H), 2.97 (t, 2H), 3.36 (s,2H), 3.98 (t, 2H), 7.50 (d, 2H), 7.88 (d, 2H), 9.98 (s, 1H), 11.45 (s,1H)

MS (ESIpos): m/z=316.8 (M+H)⁺

EXAMPLE 61-[2-(4-{[(2-Hydroxyethyl)amino]methyl}phenyl)ethyl]-1,5,7,8-tetrahydro-2H-thiopyrano-[4,3-d]pyrimidine-2,4(3H)-dione

201 mg (0.95 mmol) of sodium triacetoxyborohydride and 0.072 ml (1.26mmol) of glacial acetic acid are added to a solution of 200 mg (0.63mmol) of the compound from example 5 and 386 mg (6.3 mmol) of2-aminoethanol in 1,2-dichloroethane (20 ml). After a reaction time ofthree hours at room temperature, concentrated aqueous ammonia solutionis added and the mixture is then extracted three times withdichloromethane. The combined organic phases are washed with saturatedaqueous sodium chloride solution and dried over sodium sulfate. Afterfiltration and removal of the solvent under reduced pressure, theresulting residue is separated by chromatography on silica gel (mobilephase: dichloromethane/methanol/ammonia). This gives 170 mg (0.47 mmol,yield: 74% of theory) of the title compound as a yellow solid.

¹H NMR (300 MHz, DMSO-d₆): δ=2.52 (t, 2H), 2.68-2.89 (m, 6H), 3.33 (s,2H), 3.45 (t, 2H), 3.68 (s, 2H), 3.90 (t, 2H), 4.42 (s, 1H), 7.16 (d,2H), 7.24 (d, 2H)

MS (ESIpos): m/z=362 (M+H)⁺

EXAMPLE 71-[2-(2,4-Dimethyl-1H-imidazol-1-yl)propyl]-1,5,7,8-tetrahydro-2H-thiopyrano[4,3-d]-pyrimidine-2,4(3H)-dionea)2-[3-(2,4-Dimethyl-1H-imidazol-1-yl)propyl]-1H-isoindole-1,3(2H)-dione

A solution of 2 g (20.8 mmol) of 2,4-dimethylimidazole, 5.9 g (21.8mmol) of 3-(bromopropyl)phthalimide and 3 g (21.8 mmol) of potassiumcarbonate in DMF (30 ml) is heated at 110° C. for 2 h. After cooling toroom temperature, a little water is added and the mixture is extractedthree times with ethyl acetate. The organic phase is then washed withsaturated aqueous sodium chloride solution and dried over sodiumsulfate. Removal of the solvent under reduced pressure gives a residuewhich is directly reacted further in the next step.

b) 3-(2,4-Dimethyl-1H-imidazol-1-yl)propylamine hydrochloride

8.8 ml (42.7 mmol) of a 24% strength aqueous hydrazine hydride solutionare added to a solution of the2-[3-(2,4-dimethyl-1H-imidazol-1-yl)propyl]-1H-isoindole-1,3(2H)-dione(crude product) obtained in preparation step 1 in ethanol (50 ml), andthe reaction mixture is heated at reflux temperature for 2 h. Aftercooling of the reaction mixture to room temperature and reduction of thesolvent under reduced pressure to about a third of its volume, theresulting precipitate is filtered off and washed with a little ethanol.Concentrated aqueous hydrochloric acid (50 ml) is added to the resultingfiltrate, the precipitated solid is filtered off and washed with conc.aqueous hydrochloric acid and the resulting filtrate is removedcompletely from the solvent under reduced pressure. This gives 1.2 g(6.5 mmol, yield: 31% of theory) of the title compound which isdirectly, without further purification, reacted in the next step.

¹H NMR (200 MHz, DMSO-d₆): δ=2.05 (t, 2H), 2.21 (s, 2H), 2.58 (s, 3H),2.62-2.94 (m, 2H), 4.19 (t, 2H), 7.41 (s, 1H)

MS (ESIpos): m/z=154.1 (M+H)⁺

c)1-[3-(2,4-Dimethyl-1H-imidazol-1-yl)propyl]-1,5,7,8-tetrahydro-2H-thiopyrano[4,3-d]pyrimidine-2,4(3H)-dione

A solution of 1.2 g (6.5 mmol) of3-(2,4-dimethyl-1H-imidazol-1-yl)propylamine hydrochloride (seepreparation step 2) in about 100 ml of saturated aqueous sodiumbicarbonate solution is concentrated to dryness under reduced pressure(liberation of the amine), the residue is suspended in 50 ml of toluene,663 mg (5.7 mmol) of tetrahydrothiopyran-4-one and a spatula tip ofcamphorsulfonic acid are added and the mixture is heated under reflux ona water separator for 1.5 hours. The reaction mixture is then allowed tocool to room temperature, and 0.5 ml (6.2 mmol) of chlorocarbonylisocyanate is added. The reaction mixture is again heated at 100° C. forone hour, and, after cooling of the reaction mixture, the solvent isthen removed under reduced pressure. The resulting residue ischromatographed on silica gel (mobile phase:dichloromethane/methanol/ammonia). This gives 590 mg (1.8 mmol, yield:32% of theory) of the title compound as a beige solid.

¹H NMR (400 MHz, DMSO-d₆): δ=1.91 (t, 2H), 2.00 (s, 3H), 2.21 (s, 3H),2.78 (t, 2H), 2.84 (t, 2H), 3.27-3.49 (m, 2H), 3.73 (t, 2H), 3.84 (t,2H), 6.77 (s, 1H), 11.41 (s, 1H)

MS (ESIpos): m/z =321 (M+H)⁺

EXAMPLE 81-[3-(4-Methyl-1H-imidazol-1-yl)propyl]-1,5,7,8-tetrahydro-2H-thiopyrano[4,3-d]pyrimidine-2,4(3H)-dione

Analogously to the procedure for examples 7 a) and b),3-(4-methyl-1H-imidazol-1-yl)-1-propaneamine hydrochloride is preparedin two steps from 5 g (60.9 mmol) of 4-methyl-1H-imidazole (3.78 g, 21.5mmol, yield: 35% of theory). Analogously to the procedure for example 7c), after liberation of the amine and reaction withtetrahydrothiopyran-4-one (2.2 g, 18.97 mmol) and chlorocarbonylisocyanate (1.67 ml, 20.69 mmol) a crude product is obtained which ispurified by preparative HPLC chromatography (column: Kromasil 100 C 18,250×20 mm; mobile phase: methanol/0.2% strength aqueous trifluoroaceticacid; flow rate: 25 ml/min; UV detection at 274 nm). This gives 125 mg(0.4 mmol, yield: 2%. of theory) of the title compound as a free baseand 304 mg (0.7 mmol, yield: 4% of theory) as the correspondingtrifluoroacetate salt.

Analysis of the free base:

¹H NMR (300 MHz, DMSO-d₆): δ=1.98 (t, 2H), 2.08 (s, 3H), 2.75 (t, 2H),2.85 (t, 2H), 3.23-3.48 (m, 2H), 3.75 (t, 2H), 3.95 (t, 2H), 6.92 (s,1H), 7.59 (s, 1H), 11.49 (s, 1H)

MS (ESIpos): m/z=307 (M+H)⁺

EXAMPLE 9 1-[2-(4-Nitrophenyl)ethyl]-1,5,7,8-tetrahydro-2H-thiopyrano[4,3-d]pyrimidine-2,4(3H)-dione

A spatula tip of camphorsulfonic acid is added to a solution of 5.7 g(28.1 mmol) of 4-nitrophenylethylamine and 3.6 g (30.9 mmol) oftetrahydrothiopyran-4-one in 100 ml of toluene, and the mixture isheated under reflux on a water separator for 1.5 hours. The reactionsolution is then allowed to cool under argon, and 2.7 ml (33.8 mmol) ofchlorocarbonyl isocyanate are added at room temperature. The reactionmixture is heated at 100° C. for one hour and, after cooling to roomtemperature, the solvent is then removed under reduced pressure. Thereaction mixture is triturated with water (about 100 ml) and theprecipitated solid is filtered off, washed with a little water/diethylether and then dried under reduced pressure. This gives 7.3 g (21.9mmol, yield: 75% of theory) of the title compound as a colorless solid.

¹H NMR (300 MHz, DMSO-d₆): δ=2.78-2.90 (m, 4H), 3.01 (t, 2H), 3.30-3.42(m, 2H), 3.99 (t, 2H), 7.55 (d, 2H), 8.18 (d, 2H), 11.43 (s, 1H)

MS (ESIpos): m/z=333.8 (M+H)⁺

EXAMPLE 101-[2-(4-Aminophenyl)ethyl]-1,5,7,8-tetrahydro-2H-thiopyrano[4,3-d]pyrimidine-2,4(3H)-dione

320 mg (0.30 mmol) of palladium (10% on activated carbon) are added to asuspension of 1 g (3 mmol) of the compound from example 9 in methanol(100 ml) and tetrahydrofuran (100 ml). The reaction mixture ishydrogenated in a hydrostatic hydrogen atmosphere overnight. The mixtureis then filtered through Celite, and the filter cake is washed withmethanol. The solvent is removed under reduced pressure and theresulting residue is purified by preparative HPLC (column: Kromasil 100C 18.5 mm; 250×40 mm; mobile phase: acetonitrile/water; flow rate: 50ml/min; UV detection at 254 nm). This gives 417 mg (1.37 mmol, yield:45% of theory) of the title compound as a yellow solid.

¹H NMR (300 MHz, DMSO-d₆): δ=2.65 (t, 2H), 2.72-2.82 (m, 4H), 3.29-3.40(m, 1H), 3.82 (t, 2H), 4.92 (s, 2H), 6.49 (d, 2H), 6.86 (d, 2H), 11.42(s, 1H)

MS (ESIpos): m/z=304 (M+H)⁺

EXAMPLE 11N-{4-[2-(2,4-Dioxo-3,4,7,8-tetrahydro-2H-thiopyrano[4,3-d]pyrimidine-1(5H)-yl)ethyl]phenyl-n-tert-butyloxycarbonylglycinamide

A solution of 173 mg (0.99 mmol) of N-(tert-butoxycarbonyl)glycine, 98mg (0.73 mmol) of HOBt and 145 mg (0.76 mmol) of EDC in DMF (5 ml) isstirred at room temperature for 30 minutes. 200 mg (0.66 mmol) of thecompound from example 10, 0.22 ml (2.0 mmol) of 4-methylmorpholine and aspatula tip of DMAP are added to this solution, and the mixture isstirred at room temperature overnight. After filtration, the reactionsolution is directly separated by preparative HPLC (column: Kromasil 100C 18.5 mm; 250×40 mm; mobile phase: acetonitrile/water; flow rate: 50ml/min; UV detection at 254 nm). This gives 243 mg (0.53 mmol, yield:80% of theory) of the title compound as a colorless solid.

¹H NMR (300 MHz, DMSO-d₆): δ=1.40 (s, 9H), 2.68-2.85 (m, 6H), 3.43 (m,2H), 3.63-3.75 (m, 2H), 3.90 (t, 2H), 7.00 (t, 1H), 7.18 (d, 2H), 7.51(d, 2H), 9.90 (s, 1H)

MS (ESIpos): m/z=461 (M+H)⁺

EXAMPLE 12N-{4-[2-(2,4-Dioxo-3,4,7,8-tetrahydro-2H-thiopyrano[4,3-d]pyrimidin-1(5H)-yl)ethyl]phenylglycinamide

Trifluoroacetic acid (2 ml) is added to a solution of 200 mg (0.43 mmol)of the compound from example 11 in dichloromethane (4 ml), the mixtureis stirred at room temperature for one hour, a little water is added andthe mixture is extracted three times with dichloromethane. The combinedorganic phases are then washed with saturated aqueous sodium chloridesolution and dried over sodium sulfate. After filtration and removal ofthe solvent under reduced pressure, the resulting residue is purified bypreparative HPLC (column: Kromasil 100 C 18.5 mm; 250×40 mm; mobilephase: acetonitrile/water; flow rate: 50 ml/min; UV detection at 254nm). This gives 46 mg (0.13 mmol, yield: 29% of theory) of the titlecompound as a colorless solid.

¹H NMR (300 MHz, DMSO-d₆): δ=2.69-2.89 (m, 6H), 3.14-3.55 (m, 4H), 3.9(t, 2H), 7.16 (d, 2H), 7.57 (d, 2H)

MS (ESIpos): m/z=361 (M+H)⁺

EXAMPLE 131-[2-(4-Nitrophenyl)ethyl]-5,6,7,8-tetrahydro-2,4(1H,3H)-quinazolinedione

A spatula tip of camphorsulfonic acid is added to a mixture of 7.35 g(44.2 mmol) of 2-(4-nitrophenyl)ethylamine and 4.3 g (44.2 mmol) ofcyclohexanone in 300 ml of toluene and the mixture is heated underreflux on a water separator for 3 hours. The reaction mixture is thenallowed to cool, and 3.6 ml (44.2 mmol) of chlorocarbonyl isocyanate areadded at room temperature. The reaction mixture is heated at 130° C. forone hour and, after cooling to room temperature, the solvent is removedunder reduced pressure. The resulting residue is crystallized from ethylacetate, and the solid is filtered off with suction, washed with diethylether and dried under high vacuum. This gives 10.2 g (32.3 mmol, yield:73% of theory) of the title compound as a yellowish solid.

¹H NMR (300 MHz, DMSO-d₆): δ=1.44-1.74 (m, 4H), 2.20 (t, 2H), 2.42-2.59(m, 2H), 3.00 (t, 2H), 3.96 (t, 2H), 7.52 (d, 2H), 8.19 (d, 2H), 11.25(s, 1H)

MS (ESIpos): m/z=316 (M+H)⁺

EXAMPLE 141-[2-(4-Aminophenyl)ethyl]-5,6,7,8-tetrahydro-2,4(1H,3H)-quinazolinedione

180 mg of palladium (10% on activated carbon) are added to a suspensionof 1.8 g (5.7 mmol) of the compound from example 13 in methanol (45 ml)and tetrahydrofuran (90 ml), and the mixture is hydrogenated under ahydrostatic hydrogen atmosphere overnight. After filtration throughCelite and washing of the filter cake with methanol, the solvent isremoved under reduced pressure. The resulting residue is recrystallizedfrom ethyl acetate and the solid is filtered off, washed with diethylether and dried under high vacuum. This gives 1.0 g (3.5 mmol, yield:61% of theory) of the title compound as a colorless solid.

¹H NMR (300 MHz, DMSO-d₆): δ=1.40-1.70 (m, 4H), 2.18 (t, 2H), 2.40 (t,2H), 2.64 (t, 2H), 3.79 (t, 2H), 4.92 (s, 2H), 6.49 (d, 2H), 6.82 (d,2H), 11.20 (s, 1H)

MS (ESIpos): m/z=286 (M+H)⁺

EXAMPLE 15N-{4-[2-(2,4-Dioxo-3,4,5,6,7,8-hexahydro-1(2H)-quinazolinyl)ethyl]phenyl}-2-thiophenesulfonamide

32 mg (0.18 mmol) of 2-thiophenesulfonyl chloride are added to asolution of 50 mg (0.18 mmol) of the compound from example 14 inpyridine (2.5 ml), and the mixture is stirred at room temperatureovernight. A little water is then added to the reaction mixture, the pHis adjusted to neutral using aqueous hydrochloric acid (2 N) and themixture is extracted three times with dichloromethane. The combinedorganic phases are washed with water and saturated sodium chloridesolution and dried over sodium sulfate. Removal of the solvent underreduced pressure gives 32.5 mg (0.8 mmol, yield: 40% of theory) of thetitle compound as a colorless solid.

¹H NMR (300 MHz, DMSO-d₆): δ=1.38-1.59 (m, 4H), 2.15 (t, 2H), 2.25-2.38(m, 2H), 2.76 (t, 2H), 3.82 (t, 2H), 7.00-7.14 (m, 5H), 7.51 (d, 1H),7.89 (s, 1H), 10.37 (s, 1H), 11.21 (s, 1H)

MS (ESIpos): m/z=432.2 (M+H)⁺

Working examples 16 to 82 listed in the table below were preparedanalogously to examples 1 to 15 described above: Example calc. R_(t)(min.)/ mass found, No. mass Structure HPLC-method m/z (M + H)⁺ 16314.39

3.63 (B)   315.2 17 257.29

2.54 (E) 258 18 330.39

3.70 (E) 331 19 286.33

3.82 (E) 287 20 284.36

3.70 (B)   285.4 21 274.33

2.97 (A) 275 22 275.31

3.03 (A) 276 23 288.35

2.29 (B)   289.1 24 298.38

3.98 (B)   299.1 25 300.36

4.08 (A) 301 26 328.41

3.81 (B)   329.2 27 320.39

3.93 (B)   321.1 28 315.33

3.40 (B)   316.1 29 298.38

3.94 (B)   299.1 30 271.32

0.46 (B)   372.1 31 349.23

4.20 (C) 349 32 328.37

3.40 (B)   329.1 33 271.32

0.32 (B)   272.2 34 347.37

3.45 (A)   348.2 35 329.35

3.59 (B)   330.1 36 377.46

3.08 (B)   378.2 37 363.44

2.88 (B)   364.2 38 333.35

3.14 (A)   334.1 39 317.30

3.64 (A) 318 40 333.37

3.91 (A) 334 41 271.32

2.24 (B) 270 (M − H)⁺ 42 419.54

4.03 (C) 420 43 288.37

3.72 (A)   289.1 44 349.41

3.33 (A)   350.4 45 367.45

3.40 (A) 368 46 334.44

0.53 (B)   335.3 47 365.41

3.38 (A)   383.1 (M + NH₄)⁺ 48 351.39

3.26 (A) 352 49 306.39

0.44 (C) 307 50 367.27

4.23 (A) 367 51 298.34

3.74 (A) 299 52 293.35

2.88 (A) 294 53 306.39

3.14 (A) 307 54 327.43

3.35 (A) 328 55 318.40

3.92 (A) 319 56 275.33

2.59 (A) 276 57 313.40

3.31 (A) 314 58 371.50

2.77 (A) 372 59 345.46

0.83 (B)   346.2 60 331.44

0.81 (B)   332.3 61 385.53

3.44 (A) 386 62 442.58

3.33 (A) 443 63 387.50

3.30 (A) 388 64 303.38

3.05 (A) 304 65 337.36

3.19 (A) 333 66 289.36

2.89 (A) 290 67 289.36

2.87 (A) 290 68 430.57

3.20 (A) 431 69 443.57

3.30 (A) 444 70 388.49

3.30 (A)   389.1 71 529.66

3.80 (A)   530.4 72 368.46

3.57 (A) 369 73 444.55

3.38 (A) 445 74 400.54

3.20 (A) 401 75 429.54

3.27 (A) 430 76 292.36

2.86 (A) 293 77 320.42

3.06 (A) 321 78 348.47

3.28 (A) 349 79 334.44

3.27 (A) 335 80 357.48

3.41 (A)   358.4 81 382.49

3.50 (A)   383.3 82 340.83

3.05 (A) 341HPLC Methods:

-   (A): Mobile phase A: 0.5% HClO₄ in water; mobile phase B:    acetonitrile; gradient: 0.5 min 98% A, 2% B; 4.5 min 10% A, 90% B;    6.7 min 98% A, 2% B; flow rate: 0.75 ml/min; column temperature: 30°    C.; UV detection at 210 mn; column: Kromasil C18 (60×2 mm).-   (B): Mobile phase A: 0.1% formic acid in water; mobile phase B: 0.1%    formic acid in acetonitrile; gradient: 0 min 90% A, 10% B; 4 min 10%    A, 90% B; 6.1 min 90% A, 10% B; flow rate: 0.5 ml/min; column    temperature: 40° C.; UV detection at 210 nm; column: Symmetry C18    (150×2.1 mm).-   (C): Mobile phase A: 0.06% HCl in water; mobile phase B:    acetonitrile; gradient: 1 min 90% A, 10% B; 4 min 10% A, 90% B; flow    rate: 0.6 ml/min; column temperature: 50° C.; UV detection at 210    nm; column: Symmetry C18 (150×2.1 mm).-   (D): As for method (A), but using the following gradient: 0.5 min    98% A, 2% B; 4.5 min 10% A, 90% B; 9.2 min 98% A, 2% B.-   (E): Mobile phase A: 0.01% HCl in water; mobile phase B:    acetonitrile; gradient: 0 min 98% A, 2% B; 2.5 min 5% A, 9% B; flow    rate: 0.9-1.2 ml/min; column temperature: 70° C.; UV detection at    210 nm; column: Symmetry C18 (150×2.1 mm).    C. Working Examples of Pharmaceutical Compositions

The compounds according to the invention can be converted intopharmaceutical preparations as follows:

Tablet:

Composition:

100 mg of the compound from example 1, 50 mg of lactose (monohydrate),50 mg of corn starch (native), 10 mg of polyvinylpyrrolidone (PVP 25)(from BASF, Ludwigshafen, Germany) and 2 mg of magnesium stearate.Tablet weight 212 mg. Diameter 8 mm, radius of the curvature 12 mm.

Preparation:

The mixture of active compound, lactose and starch is granulated using a5% by weight strength solution of the PVP in water. After drying, thegranules are mixed with the magnesium stearate for 5 min. This mixtureis tabletted in a customary tablet press (dimensions of the tablet seeabove). As a guideline for tabletting, a compaction force of 15 kN isused.

Orally Administrable Suspension:

Composition:

1000 mg of the compound of example 1, 1000 mg of ethanol (96%), 400 mgof Rhodigel (xanthan gum from FMC, Pennsylvania, USA), and 99 g ofwater. A single dose of 100 mg of the compound according to theinvention corresponds to 10 ml of oral suspension.

Preparation:

The Rhodigel is suspended in ethanol and the active compound is added tothe suspension. The water is added with stirring. The mixture is stirredfor about 6 h, until the swelling of the Rhodigel is complete.

1. A compound of the formula (I)

in which A represents —CH₂—, —O— or —S—, R¹ represents hydrogen oralkoxycarbonyl, R² represents aryl or heteroaryl which for their partmay be substituted up to three times, independently of one another, bysubstituents selected from the group consisting of nitro, halogen,cyano, aryl, hetaryl, benzyl, alkyl, cycloalkyl, alkoxy, formyl,alkoxycarbonyl, trifluoromethyl, di- and trifluoromethoxy, hydroxyl,amino, alkylamino, aminosulfonyl, alkylsulfonylamino, arylsulfonylamino,hetarylsulfonylamino, —Y—OR³ and —Y—NR³R⁴, in which Y represents CH₂,C(═O) or *—NH—C(═O)—CHR⁵—, in which * represents the point of attachmentto the aromatic or heteroaromatic radical, R³ and R⁴ independently ofone another represent hydrogen, optionally hydroxyl- oramino-substituted alkyl, alkenyl or alkoxycarbonyl, or R³ and R⁴together with the nitrogen atom to which they are attached form a 5- to7-membered heterocycle which may contain a further heteroatom N, O or Sin the ring and which is optionally substituted by amino, hydroxyl,alkoxycarbonyl or alkyl which for its part may be substituted byhydroxyl or amino, R⁵ represents hydrogen or alkyl which for its partmay be substituted by phenyl, 4-hydroxyphenyl, amino, hydroxyl,carboxyl, guanidino, imidazolyl, indolyl, mercapto or methylthio, or R³and R⁵ together represent propane-1,3-diyl or butane-1,4-diyl, and Xrepresents alkanediyl in which one methylene group may be replaced by anoxygen atom or a salt, a solvate or a solvate of a salt thereof.
 2. Acompound as claimed in claim 1, in which A represents —CH₂— or —S—, R¹represents hydrogen, R² represents phenyl, pyridyl, pyrazolyl orimidazolyl which for their part may be substituted up to three times,independently of one another, by substituents selected from the groupconsisting of nitro, halogen, phenyl, benzyl, (C₁-C₄)-alkyl,(C₁-C₄)-alkoxy, formyl, (C₁-C₄)-alkoxycarbonyl, amino, hydroxyl,aminosulfonyl and —Y—NR³R⁴, in which Y represents CH₂, *—NH—C(═O)—CH₂—or *—NH—C(═O)—CH(CH₃)—, in which * represents the point of attachment tothe aromatic or heteroaromatic radical, R³ and R⁴ independently of oneanother represent hydrogen, optionally hydroxyl- or amino-substituted(C₁-C₄)-alkyl, (C₂-C₄)-alkenyl or (C₁-C₄)-alkoxycarbonyl or R³ and R⁴together with the nitrogen atom to which they are attached form a 5- to7-membered heterocycle which may contain a further heteroatom N or O inthe ring and which is optionally substituted by amino, hydroxyl,(C₁-C₄)-alkoxycarbonyl or (C₁-C₄)-alkyl which for its part may besubstituted by hydroxyl or amino, and X represents (C₁-C₄)-alkanediyl ora salt, a solvate or a solvate of a salt thereof.
 3. A compound asclaimed in claim 1, in which A represents —S—, R¹ represents hydrogen,R² represents phenyl or imidazolyl which for their part may besubstituted up to three times, independently of one another, bysubstituents selected from the group consisting of nitro, fluorine,chlorine, bromine, methyl, ethyl, isopropyl, methoxycarbonyl and—Y—NR³R⁴, in which Y represents CH₂ or *—NH—C(═O)—CH₂—, in which *represents the point of attachment to phenyl or imidazolyl, R³ and R⁴independently of one another represent hydrogen, methyl, ethyl,isopropyl, which are optionally substituted by hydroxyl or amino, orrepresent allyl or methoxycarbonyl, or R³ and R⁴ together with thenitrogen atom to which they are attached represent pyrrolidin-1-yl,piperidin-1-yl, piperazin-1-yl, 4-methylpiperazin-1-yl,4-(2-hydroxyethyl)piperazin-1-yl or morpholin-4-yl and X representsethane-1,2-diyl, propane-1,3-diyl or butane-1,4-diyl or a salt, asolvate or a solvate of a salt thereof.
 4. (canceled)
 5. A process forpreparing compounds of the formula (I) as defined in claim 1,characterized in that compounds of the formula (II)

in which A is as defined in claim 1, are reacted with compounds of theformula (III)H₂N—X—R   (III), in which X and R² are as defined in claim 1, to givecompounds of the formula (IV)

in which A, X and R are as defined in claim 1, then reacted withchlorocarbonyl isocyanate to give compounds of the formula (Ia)

in which A, X and R² are as defined in claim 1 and R¹ representshydrogen, and compounds of the formula (Ia) are, if appropriate, reactedwith compounds of the formula (V)R¹-Z   (V), in which R¹ is as defined in claim 1, but is not hydrogen,and Z represents a leaving group, to give compounds of the formula (D)in which R¹ is not hydrogen.
 6. A composition, comprising at least onecompound of the formula (I) as defined in claim 1 and at least onefurther active compound.
 7. A composition, comprising at least onecompound of the formula (I) as defined in claim 1 and one or morepharmaceutically acceptable auxiliaries.
 8. A method of treatingischemia and reperfusion damage, comprising administering to a patientin need thereof an effective amount of a compound of formula (I) asdefined in claim 1.